title: Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors.
abstract: Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53704, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Thliveris
authors.forename: Brittany
authors.initials: B
authors.lastname: Schwefel
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.forename: Lauren
authors.initials: L
authors.lastname: Plesh
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Zahm
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Leystra
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.forename: Richard B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000473:pathology; D017491:Genes, APC; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: clonal interactions; colon cancer; mouse model; spatial statistics